Methods

Post hoc subgroup analyses were performed using data from a multicenter, randomized, double-blind, placebo-controlled, parallel group Phase 2b/3 study conducted at 36 sites in the United States. The protocol was approved by the Quorum Review Institutional Review Board (Seattle, WA). All participants gave written informed consent prior to any study procedures being performed. Detailed methods have been previously reported.[23] Eligible patients had experienced 2 to 8 migraine headaches (with or without aura) during a 28-day run-in period. On the first day of the run-in period, patients declared their MBS other than pain (nausea [with or without vomiting], photophobia, or phonophobia), that is most bothersome most of the time with their migraine headaches. Patients were randomly assigned in a 1:1:1:1 ratio, stratified by MBS, to receive ADAM zolmitriptan 1, 1.9, 3.8 mg, or placebo to treat 1 moderate or severe headache. Symptoms were recorded using an e-diary.

In accordance with the co-primary endpoints in the ZOTRIP trial, which were selected based on recently issued guidance by the US Food and Drug Administration,[25] we analyzed pain freedom and MBS freedom at 2 hours post-dose in patients whose migraine headaches might be characterized as more difficult to treat. Specifically, we evaluated those with severe pain at the time of treatment, those whose headaches were associated with nausea at the time of treatment, headaches treated ≥2 hours after onset, and headaches present upon awakening in the morning. Data are only reported here for the ADAM zolmitriptan 3.8 mg dose, which showed a significant treatment effect vs placebo for the co-primary endpoints of pain freedom and MBS freedom at 2 hours post-dose.

Statistical Analysis

In the original ZOTRIP trial, sample size (n = 360) was determined by estimating that 15% of patients receiving placebo and 35% of those receiving active treatment would achieve freedom from each co-primary endpoint, pain or MBS, at 2 hours post-dose. A stratified chi-square test was used to estimate the number needed to detect this treatment difference with 80% statistical power and 5% 2-sided significance level. Allowing for 15% dropout rate, this equated to approximately 90 subjects per group.

Analysis of each subgroup was performed via the Cochran–Mantel–Haenszel test stratified by MBS. Last observation carried forward was used to impute missing data. Subgroup by treatment interactions were formally assessed using logistic regression on the full sample with the categorical effects of treatment, MBS, subgroup, and subgroup by treatment interaction. All statistical tests were 2-sided and tested at a significance level of .05. No adjustments to P values were made for the multiple post hoc analyses performed.

All authors had full access to all study data. Analyses were performed using Statistical Analysis System (SAS®) software version 9.4 (SAS Institute, Cary, NC, USA).